Factors Associated with Bovine Neonatal Pancytopenia (BNP) in Calves: A Case-Control Study

Lambton, Sarah L; Colloff, Adrian; Smith, Richard P.; Caldow, George; Scholes, S. F. E.; Willoughby, Kim; Howie, Fiona; Ellis‐Iversen, Johanne; David, Graham; Cook, A. J. C.; Holliman, Andrew

doi:10.1371/journal.pone.0034183

Cited by 17 publications

(18 citation statements)

References 15 publications

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“…Of all the risk factors, the highest odds ratio was for using PregSure vaccine either alone or in combination with other BVDV vaccines. The association between the use of PregSure and case-control status is consistent with results of previous case-control studies, which reported odds ratios of 40.8 and 1292 for the use of PregSure [17, 19] and of other studies that examined the pathogenesis of BNP [13, 21–23, 27–30]. This factor was also found to be significantly associated with the occurrence of BNP in our analysis at animal level [24].…”

Section: Discussionsupporting

confidence: 91%

Herd-level animal management factors associated with the occurrence of bovine neonatal pancytopenia in calves in a multi-country study

et al. 2017

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Since 2007, mortality associated with a previously unreported haemorrhagic disease has been observed in young calves in several European countries. The syndrome, which has been named ‘bovine neonatal pancytopenia’ (BNP), is characterised by thrombocytopenia, leukocytopenia and a panmyelophthisis. A herd-level case-control study was conducted in four BNP affected countries (Belgium, France, Germany and the Netherlands) to identify herd management risk factors for BNP occurrence. Data were collected using structured face-to-face and telephone interviews of farm managers and their local veterinarians. In total, 363 case farms and 887 control farms were included in a matched multivariable conditional logistic regression analysis. Case-control status was strongly associated with the odds of herd level use of the vaccine PregSure® BVD (PregSure, Pfizer Animal Health) (matched adjusted odds ratio (OR) 107.2; 95% CI: 41.0–280.1). This was also the case for the practices of feeding calves colostrum from the calf’s own dam (OR 2.0; 95% CI: 1.1–3.4) or feeding pooled colostrum (OR 4.1; 95% CI: 1.9–8.8). Given that the study had relatively high statistical power and represented a variety of cattle production and husbandry systems, it can be concluded with some confidence that no other herd level management factors are competent causes for a sufficient cause of BNP occurrence on herd level. It is suggested that genetic characteristics of the dams and BNP calves should be the focus of further investigations aimed at identifying the currently missing component causes that together with PregSure vaccination and colostrum feeding represent a sufficient cause for occurrence of BNP in calves.

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Section: Discussionsupporting

confidence: 91%

Herd-level animal management factors associated with the occurrence of bovine neonatal pancytopenia in calves in a multi-country study

et al. 2017

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“…It is characterised by profound depletion of peripheral leukocytes and thrombocytes and bone marrow trilineage hypoplasia, and is mediated by the ingestion of alloantibodies in colostrum [4][5][6]. BNP has been linked epidemiologically to vaccination of the dams of affected calves with a particular inactivated Bovine Viral Diarrhoea Virus (BVDV) vaccine (Pregsure BVD, Pfizer Animal Health) which incorporates a novel adjuvant formulation [7][8][9]. However the incidence of clinical BNP has been reported to be only 0.0016% per dose of vaccine sold [10].…”

Section: Introductionmentioning

confidence: 99%

Haematopoietic depletion in vaccine-induced neonatal pancytopenia depends on both the titre and specificity of alloantibody and levels of MHC I expression

Bell

MacHugh

Connelley

et al. 2015

Vaccine

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Bovine Neonatal Pancytopenia (BNP) is a disease of calves characterised by haematopoietic depletion, mediated by ingestion of alloantibodies in colostrum. It has been linked epidemiologically to vaccination of the dams of affected calves with a particular vaccine (Pregsure) containing a novel adjuvant. Evidence suggests that BNP-alloantibodies are directed against MHC I molecules, induced by contaminant bovine cellular material from Madin-Darby Bovine Kidney (MDBK) cells used in the vaccine's production. We aimed to investigate the specificity of BNP-alloantibody for bovine MHC I alleles, particularly those expressed by MDBK cells, and whether depletion of particular cell types is due to differential MHC I expression levels. A complement-mediated cytotoxicity assay was used to assess functional serum alloantibody titres in BNP-dams, Pregsure-vaccinated dams with healthy calves, cows vaccinated with an alternative product and unvaccinated controls. Alloantibody specificity was investigated using transfected mouse lines expressing the individual MHC I alleles identified from MDBK cells and MHC I-defined bovine leukocyte lines. All BNP-dams and 50% of Pregsure-vaccinated cows were shown to have MDBK-MHC I specific alloantibodies, which cross-reacted to varying degrees with other MHC I genotypes. MHC I expression levels on different blood cell types, assessed by flow cytometry, were found to correlate with levels of alloantibody-mediated damage in vitro and in vivo. Alloantibody-killed bone marrow cells were shown to express higher levels of MHC I than undamaged cells. The results provide evidence that MHC I-specific alloantibodies play a dominant role in the pathogenesis of BNP. Haematopoietic depletion was shown to be dependent on the titre and specificity of alloantibody produced by individual cows and the density of surface MHC I expression by different cell types. Collectively, the results support the hypothesis that MHC I molecules originating from MDBK cells used in vaccine production, coupled with a powerful adjuvant, are responsible for the generation of pathogenic alloantibodies.

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“…The underlying lesion is a dramatic bone marrow injury with depletion of hematopoietic cells and their precursors. There is an association with maternal vaccination with an inactivated bovine virus diarrhoea (BVD) vaccine (Pregsure BVD, Pfizer) [6,7]; which was voluntarily withdrawn by the manufacturer in Europe in 2010, but BNP cases continue in calves born to or ingesting colostrum derived from some vaccinated animals. The syndrome can be reproduced by feeding of colostrum from cows which have borne affected calves (BNP dams) to unrelated calves [8-10], and disease can be prevented by colostrum substitution [11].…”

Section: Introductionmentioning

confidence: 99%

Demonstration of early functional compromise of bone marrow derived hematopoietic progenitor cells during bovine neonatal pancytopenia through in vitro culture of bone marrow biopsies

et al. 2012

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BackgroundBovine neonatal pancytopenia (BNP) is a syndrome characterised by thrombocytopenia associated with marked bone marrow destruction in calves, widely reported since 2007 in several European countries and since 2011 in New Zealand. The disease is epidemiologically associated with the use of an inactivated bovine virus diarrhoea (BVD) vaccine and is currently considered to be caused by absorption of colostral antibody produced by some vaccinated cows (“BNP dams”). Alloantibodies capable of binding to the leukocyte surface have been detected in BNP dams and antibodies recognising bovine MHC class I and β-2-microglobulin have been detected in vaccinated cattle. In this study, calves were challenged with pooled colostrum collected from BNP dams or from non-BNP dams and their bone marrow hematopoietic progenitor cells (HPC) cultured in vitro from sternal biopsies taken at 24 hours and 6 days post-challenge.ResultsClonogenic assay demonstrated that CFU-GEMM (colony forming unit-granulocyte/erythroid/macrophage/megakaryocyte; pluripotential progenitor cell) colony development was compromised from HPCs harvested as early as 24 hour post-challenge. By 6 days post challenge, HPCs harvested from challenged calves failed to develop CFU-E (erythroid) colonies and the development of both CFU-GEMM and CFU-GM (granulocyte/macrophage) was markedly reduced.ConclusionThis study suggests that the bone marrow pathology and clinical signs associated with BNP are related to an insult which compromises the pluripotential progenitor cell within the first 24 hours of life but that this does not initially include all cell types.

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Factors Associated with Bovine Neonatal Pancytopenia (BNP) in Calves: A Case-Control Study

Cited by 17 publications

References 15 publications

Herd-level animal management factors associated with the occurrence of bovine neonatal pancytopenia in calves in a multi-country study

Herd-level animal management factors associated with the occurrence of bovine neonatal pancytopenia in calves in a multi-country study

Haematopoietic depletion in vaccine-induced neonatal pancytopenia depends on both the titre and specificity of alloantibody and levels of MHC I expression

Demonstration of early functional compromise of bone marrow derived hematopoietic progenitor cells during bovine neonatal pancytopenia through in vitro culture of bone marrow biopsies

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